Microbicides

Microbicides are substances capable of protecting people from infection
by microbes, such as viruses or bacteria, by either directly killing or
disabling the microbes or physically preventing them from entering human cells.
In the context of HIV prevention, the term microbicide generally refers
specifically to products that are being designed for topical (vaginal or
rectal) application
to reduce the user’s risk of acquiring HIV and possibly other sexually
transmitted infections (STIs)1 during intercourse. When
interest in this potential HIV-prevention strategy arose in the late 1980s,
they were called ‘virucides’. The term 'microbicides' has since replaced
'virucides' to include products that could be active against a wide range of
infections, not just viruses.

In
July 2010, for the first time, a microbicide was pronounced to be both safe and
effective. It is a vaginal gel containing an anti-retroviral drug called
tenofovir and its properties and effectiveness are described below (see CAPRISA trial: the first microbicide proven to be effective). In the
previous two decades, dozens of other candidate microbicides had been tested
prior to this breakthrough. This rate of progress is characteristic of new drug
development: literally hundreds, and sometimes thousands, of compounds are
typically considered for each one that is ultimately approved for human use. In
the case of microbicide research, however, the challenge of finding a
successful product has been complicated by two distinctive factors:

The difficulty of finding a product that can disable HIV while still being safe
enough to apply frequently (daily or more often) to mucous membranes over time

Chronic underfunding of the field, since private pharmaceutical companies and
other developers have shown little interest in investing in such products.

In 2008, a total of US$244 million supported
microbicide research and development (R&D) globally, 85% being contributed by governments and
multilaterals, 14% by the philanthropic sector and 1% by the commercial sector.
By comparison, the 2008 investment in HIV vaccine R&D stood at US$868 million, with 84% contributed by
governments and multilaterals, 12% by philanthropies and 4% by the commercial
sector. Even with a comparable distribution of funding sources, microbicides
received little more than a quarter of the support provided to vaccines. In
2004, about five times more was spent on vaccine R&D (US$933 million) than
on microbicides (US$221 million).2

Frustration about underfunding of the microbicides field persists to
this day. Dr Robin Shattock, in his opening plenary talk for the Microbicides
2010 conference, noted that the Thai vaccine trial (RV144) results had
motivated AIDS vaccine researchers and advocates to demand enough resources to
launch a Phase II vaccine trial every year. But, he added, “where is the money
to see efficacy trials for [microbicidal] entry inhibitors? Where is the
efficacy funding to see [microbicide] trials on combinations? I don’t see the
microbicide field standing up and lobbying hard enough to do more clinical
trials to get that human data that will inform the basic science.”3

Corporate sector investment has been miniscule because HIV vaccines and
microbicides are thought unlikely to be highly profitable. As the Global
Campaign for Microbicides notes: “microbicides are a classic ‘public health good’, an innovation that would yield
enormous returns to society in terms of productivity and health benefits, but
where the incentive structure of the private market fails to drive investment.
Contraceptives and vaccines to prevent the diseases of poverty such as malaria
are other public health goods.”4

Despite this, the prospects for developing at least partially effective
microbicides are good, given the growing body of scientific expertise and
political will that supports their development. The field’s main focus is on
microbicides for vaginal use, a technically simpler challenge than designing
safe and effective products for rectal use. Rectal microbicide R&D is also
underway, however, and is attracting increased attention as research indicates
that anal intercourse among heterosexuals may account for a larger share of HIV
transmission than previously supposed.5

Both heterosexuals and gay men will likely experiment with rectal
application of the first microbicides that become publicly available, just as
they did with condoms. For this reason, products designed for vaginal use must
also be tested for rectal safely so that, at minimum, labelling language can
warn users against applying them rectally if they are shown to damage rectal
tissue.

Undertaken in the late 1980s, the first microbicide research began with
testing the currently available spermicides (contraceptives designed to kill
sperm) to see if any were effective against HIV. Nonoxynol-9, the spermicidal
agent in most non-prescription contraceptive products (including gels, foams
and films), destroys HIV, but was proven ineffective as a microbicide because
frequent use of it can irritate vaginal tissue and potentially exacerbate HIV
risk.6

The development of ‘dual protection’ microbicides (products providing
both microbicidal and contraceptive protection) is still a goal of the field,
one that may be achieved by adding contraceptive agents to a proven
microbicide, if no compounds emerge that are safe for frequent use while still
active against both HIV and sperm. Social scientists have established that
demand exists both for dual-protection products and for microbicides that are
not contraceptive.7,8

Since condoms are inherently contraceptive, a non-contraceptive
microbicide would offer women the novel option of reducing their HIV risk
whilst allowing for the possibility of pregnancy - a welcome alternative to women who desire
pregnancy for their own reasons, to satisfy a partner or because of cultural
expectations. A non-contraceptive microbicide that is bi-directional could also
help HIV-positive women conceive with little risk of endangering HIV-negative
partners.

A bi-directional microbicide would be one that not
only protected the person applying it but also her or his partner. Thus, an HIV-positive
woman might use a bi-directional microbicide to reduce her partner’s risk of
becoming infected by HIV in her vaginal secretions, as well as to reduce her
own risk of acquiring another strain of HIV if her partner were also HIV-positive.
The possibility of bi-directional protection is of great interest to many microbicide
advocates, especially those living with HIV.9 To
determine its feasibility, however, we must first find a product that helps HIV-negative
people to stay negative (primary prevention). Testing that product’s capacity
for secondary prevention (blocking onward transmission from a positive partner)
will require a different type of trial, one that enrolls serodiscordant couples
rather than HIV-negative individuals. Due to the added complexity and cost of
such trials, they will only be undertaken on products already known to work for
primary prevention.

This issue is further complicated by the fact that most of the
microbicide candidates now in clinical trials are antiretroviral-based. If used
by people living with HIV who are not receiving antiretroviral combination
therapy (such as by those unaware of their HIV infection), such compounds could
lead to the development of drug-resistant HIV. It is likely that antiretroviral
(ARV)-based microbicides will only be licensed for use by prescription (based
on an HIV-negative test result) until more is known about whether, in fact, they
could trigger the emergence of resistant virus when used by people living with
HIV.

Microbicides are being developed in a range of formulations. The early,
non-ARV-based candidates were gels inserted by applicator or applied to a
vaginal diaphragm. Although five of these entered late-stage effectiveness
trials, none were successful.

The
current generation of products are taking a variety of forms, some coitally
dependent (to be applied before sex) and some not. These include gels,
dissolving films and tablets, and vaginal rings designed to gradually release the
microbicidal drug in the vagina for a month or more. HIV prevention is the
primary goal for all of them, although secondary endpoints such as STI and/or
pregnancy prevention are also being evaluated. When the first generation of
products proved unsuccessful, the field shifted its focus to higher potency,
ARV-based candidates, with the assumption that – once something is found to
work against HIV – it can become the basis for combination products that also
offer contraceptive and/or broader-spectrum STI-prevention benefits.

Acknowledgements

Written by: Anna Forbes

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

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This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends
checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member
of your healthcare team for advice tailored to your situation.